Abstract
Objectives: Normal cellular function requires a rate of ATP production sufficient to meet demand. In most neurodegenerative diseases (including Amyotrophic Lateral Sclerosis [ALS]), mitochondrial dysfunction is postulated raising the possibility of impaired ATP production and a need for compensatory maneuvers to sustain the ATP production/demand balance. We investigated intermediary metabolism of neurons expressing familial ALS (fALS) genes and interrogated the functional consequences of glycolysis genes in fitness assays and neuronal survival. Methods: We created a pure neuronal model system for isotopologue investigations of fuel utilization. In a yeast platform we studied the functional contributions of glycolysis genes in a growth fitness assay iafter expressing of a fALS gene. Results: We find in our rodent models of fALS, a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics, and redox status, thus supporting the notion that gross mitochondrial function is not compromised in neurons soon after expressing fALS genes. Genetic loss-of-function manipulation of individual steps in the glycolysis and the pentose phosphate pathway blunt the negative phenotypes seen in various fALS models. Conclusions: We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful.
| Original language | English (US) |
|---|---|
| Article number | 101468 |
| Journal | Molecular Metabolism |
| Volume | 60 |
| DOIs | |
| State | Published - Jun 2022 |
Funding
This work was supported by the National Public Health Service ( NS05225 and NS087077 , R.G.K.; R00NS109252 , Y.C.W.; CA197532 and AG049665 to N.S.C.), the Heather Koster Family Charitable Fund and the Les Turner ALS Foundation . R.P.C. was supported by a Northwestern University Pulmonary and Critical Care Department Cugell predoctoral fellowship. The 13 C-enrichments (APEs), PPP rates, and metabolite profiles were determined by the Director and members of the Metabolomics Core Facility at the Children's Hospital of Philadelphia, and we thank Ilana Nissim, Yevgeny Daikhin and Oksana Horyn for their expert contributions to these studies; Christopher Link for sharing several strains of C. elegans, Joshua Rabinowitz for the gift of G6PDi-1, Richard Kibbey for expert advice and members of the Kalb lab for fruitful discussions during the performance of these studies. We worked to ensure sex balance in the selection of subjects and experimental samples throughout this project. T.B.B. self-identifies as an underrepresented minority, and is funded by an NIH Diversity Research Supplement from the National Institute of Neurological Disorders and Stroke (attached to R00NS109252 (Y.C.W.). None of the other authors of this manuscript self-identify as an underrepresented ethnic minority, a member of the LGBTQ+ community, living with a disability or received support from a program designed to increase minority representation in science. We actively worked to promote gender balance in our reference list. We worked to ensure sex balance in the selection of subjects and experimental samples throughout this project. T.B.B. self-identifies as an underrepresented minority, and is funded by an NIH Diversity Research Supplement from the National Institute of Neurological Disorders and Stroke (attached to R00NS109252 (Y.C.W.). None of the other authors of this manuscript self-identify as an underrepresented ethnic minority, a member of the LGBTQ+ community, living with a disability or received support from a program designed to increase minority representation in science. We actively worked to promote gender balance in our reference list.This work was supported by the National Public Health Service (NS05225 and NS087077, R.G.K.; R00NS109252, Y.C.W.; CA197532 and AG049665 to N.S.C.), the Heather Koster Family Charitable Fund and the Les Turner ALS Foundation. R.P.C. was supported by a Northwestern University Pulmonary and Critical Care Department Cugell predoctoral fellowship. The 13C-enrichments (APEs), PPP rates, and metabolite profiles were determined by the Director and members of the Metabolomics Core Facility at the Children's Hospital of Philadelphia, and we thank Ilana Nissim, Yevgeny Daikhin and Oksana Horyn for their expert contributions to these studies; Christopher Link for sharing several strains of C. elegans, Joshua Rabinowitz for the gift of G6PDi-1, Richard Kibbey for expert advice and members of the Kalb lab for fruitful discussions during the performance of these studies.
Keywords
- ATP
- G6PDH
- Glycolysis
- Neuron
- Redox
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology